Prostate Cancer and Prostatic Diseases (2013) 16, 7 -- 15 & 2013 Macmillan Publishers Limited All rights reserved 1365-7852/13 www.nature.com/pcan REVIEW New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists ND Shore1, P-A Abrahamsson2, J Anderson3, ED Crawford4 and P Lange5 Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors’ therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability. Prostate Cancer and Prostatic Diseases (2013) 16, 7--15; doi:10.1038/pcan.2012.25; published online 3 July 2012 Keywords: androgen deprivation therapy; gonadotrophin-releasing hormone; agonists; antagonists INTRODUCTION increase in ADT utilization highlights the importance of strategies Androgen deprivation therapy (ADT) is first-line treatment for to reduce AEs associated with testosterone suppression. advanced/metastatic prostate cancer (PCa) and recommended This review compares ADT delivered by GnRH agonists and antagonists and assesses the potential future role of GnRH before, during or after definitive radiotherapy for intermediate and 1--3 antagonists in PCa therapy. Novel strategies to minimize the AE high-risk localized PCa. ADT is also commonly used for short risk of testosterone reduction are also explored. periods to shrink prostate volume in patients contemplating interstitial seed implantation of PCa,2,4 in glands 450 g, albeit this indication does not have a US Food and Drug Administration (FDA) METHODS or European Medicines Agency (EMEA) labelled indication. ADT A PubMed search was conducted using the search terms ‘abarelix’ [title], may be accomplished with bilateral orchiectomy or via gonado- ‘degarelix’ [title], ‘cetrorelix’ [title], ‘ozarelix’ [title], ‘teverelix’ [title], ‘acycline’ trophin-releasing hormone (GnRH) agonists or antagonists. [title], to identify published studies on GnRH antagonists for PCa therapy. GnRH agonists became the leading ADT due to the reduced PubMed searches were also conducted using the search terms ‘inter- psychological morbidity and almost equivalent efficacy to surgical mittent androgen deprivation therapy’ [title]; ‘androgen deprivation castration.1 However, agonists display several shortcomings therapy’ [title] AND ‘prostate cancer’ [title] (limit: reviews); and ‘androgen including testosterone surge/microsurges.1,5 GnRH antagonists deprivation therapy’ AND ‘prostate cancer’ AND ‘metabolic’ OR ‘cardiovas- were developed with a view toward overcoming the physiologic cular’ OR ‘bone health’ (limit: reviews). In addition, these references were drawbacks of agonists. supplemented by publications identified from the ‘more like this’ search Irrespective of how it is achieved, testosterone suppression option on PubMed, bibliographies of review articles and the authors’ causes adverse events (AEs), e.g. hot flushes, osteoporosis and personal knowledge of this therapy area. The articles identified were cardiometabolic effects.6 PSA testing has increased the proportion scrutinized and those publications considered most relevant to a of PCa patients diagnosed at earlier stages. The consequent discussion of a comparison of ADT delivered by GnRH agonists and 1Carolina Urologic Research Center, Myrtle Beach, SC, USA; 2Department of Urology, Malmo¨-Lund University Hospital, Malmo¨, Sweden; 3Department of Urology, Royal Hallamshire Hospital, Sheffield, UK; 4Department of Urology, University of Colorado at Denver, Denver, CO, USA and 5Institute for Prostate Cancer Research, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Correspondence: Dr ND Shore, Atlantic Urology Clinics, 823 82nd PKWY, Myrtle Beach, South Carolina 29572, USA. E-mail: [email protected] Received 6 March 2012; revised 29 May 2012; accepted 29 May 2012; published online 3 July 2012 ADT in advanced prostate cancer ND Shore et al 8 antagonists, the potential future role of GnRH antagonists in PCa therapy, antagonists there is a rapid and sustained suppression in LH, and novel strategies to minimize the AE risk of testosterone reduction, testosterone, DHT12,19 and FSH.12,20 were included in the review. Pharmacological profiles These distinct modes of action produce different biochemical GnRH AGONISTS AND ANTAGONISTS effects (Table 2). The initial agonist-induced testosterone surge Mechanism of action can exacerbate clinical symptoms in advanced PCa21 and delay GnRH, secreted in pulses from the hypothalamus, stimulates the therapeutic effect (agonists generally suppress testosterone to pituitary release of luteinizing hormone (LH) and follicle stimulat- o0.5 ng/ml (o1.7 nmol/l) within 3--4 weeks). Indeed, an appreci- ing hormone (FSH). LH subsequently stimulates testosterone able proportion of patients (B5--17%) receiving GnRH agonists fail secretion, predominantly by the testes (Figure 1).8,9 to achieve castrate testosterone p0.5 ng/ml.22 Testosterone GnRH agonists and antagonists exhibit different mechanisms of microsurges associated with repeat injections also occur with action. Agonists bind to GnRH receptors and produce an initial agonists.11,23 In a study with goserelin, microsurges (testosterone intense stimulation. This causes marked increases in LH, FSH surges above a castration threshold of 18.5 ng/dl (0.185 ng/ml) and testosterone. Sustained pituitary overstimulation will after X1 repeat injections) occurred in 17.7--27% of patients.5 The eventually down-regulate/desensitize GnRH receptors with a clinical implications of microsurges are currently unclear. consequent decrease in hormone levels.10 In contrast, antagonists Loss of GnRH receptor sensitivity during long-term agonist block receptors, immediately stopping LH secretion, producing therapy can allow renewed testosterone production manifesting rapid testosterone suppression without the initial LH and as late breakthrough testosterone escapes.22 In 73 patients with testosterone surge.11 non-metastatic PCa receiving agonists (38.4% also received The overall effect of ADT on hormone levels in PCa differs bicalutamide), duration of androgen-independent progression- between treatments (Table 1). Orchiectomy reduces testosterone free survival (PFS) was correlated to the extent of testosterone and dihydrotestosterone (DHT) but is accompanied by significant breakthrough escape.24 Mean PFS was significantly lower in rises in LH and FSH.15,16 In contrast, GnRH agonists cause an initial patients with breakthrough testosterone 40.32 ng/ml versus surge in LH, FSH, testosterone and DHT; over time these hormones those not experiencing breakthrough escape (88 versus 137 are suppressed.11,17 However, FSH gradually rises during GnRH months, Po0.003). agonist treatment and FSH ‘escapes’ occur.11,18 With GnRH GnRH antagonists achieve castration faster than agonists11,25 and may offer better testosterone control, in terms of the absence of initial testosterone surge or subsequent microsurges.11 Long- term testosterone control has been suggested to reduce mortality risk among patients with metastatic disease.26 In 129 patients with metastatic PCa receiving a GnRH agonist, those with high testosterone at 6 months had a 1.33-fold increase in mortality risk. GnRH antagonists cause profound and persistent FSH suppression11,20 compared with partial FSH suppression with agonists.27--29 The therapeutic advantage of persistent FSH suppression with antagonists is not fully understood. However, several studies have linked FSH with PCa. Thus, FSH stimulates PCa cell growth in vitro.30 FSH receptors